CN107847435A - The pharmaceutical preparation that inflammatory for treating rectum changes - Google Patents
The pharmaceutical preparation that inflammatory for treating rectum changes Download PDFInfo
- Publication number
- CN107847435A CN107847435A CN201680039904.2A CN201680039904A CN107847435A CN 107847435 A CN107847435 A CN 107847435A CN 201680039904 A CN201680039904 A CN 201680039904A CN 107847435 A CN107847435 A CN 107847435A
- Authority
- CN
- China
- Prior art keywords
- suppository
- preparation
- budesonide
- hard fat
- pharmaceutical preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to the pharmaceutical preparation for rectally of stable storing, it includes budesonide or its pharmaceutically at least 80 weight % hard fat or the mixture of different hard fats of compatible salt or derivative and the gross weight based on the preparation and at least one compatible antioxidant therewith.
Description
The chronic inflammatory disease of intestines and stomach is referred to as Crohn disease and ulcerative colitis.The teiology of the disease is
Unknown, although often assuming the autoimmunity aspect of the disease.Disease " Crohn disease " can include various clinical symptoms, and
And the disease can be located at the different parts of small intestine and large intestine.Ulcerative colitis is to be essentially limited to the inflammatory bowel of large intestine
Tract disease.The disease is characterised by the main mucous layer for influenceing colon and also influences the recurrence of the submucosa of colon once in a while
Property inflammation.Acute inflammation is characterised by chronic diarrhea or constipation, intestinal bleeding, spasm and stomachache.
Once in a while, differentiation is made for proctitis ulcerosa, it is considered as the relatively mild form of ulcerative colitis.It is right
In the treatment of the disease, the preparation of the Orally-administrable of particular formulation can be used.However, due to abdomen often related to disease
Rush down, oral administration can be unfavorable.
In the prior art it is also known that can rectally preparation.Gross et al.,
Aliment.Pharmacol.Ther.2006,23,303-312 is in therapeutic activity proctitis ulcerosa or proctosigmoiditis
Aspect compares budesonide (budesonide) foaming agent (foam) and budesonide (budesonide) enema.
(Gastroenterology, Vol.104 (4, Suppl.) 1993) have proposed containing 5- ammonia Belluzzi et al.
The suppository of base salicylic acid or budesonide.The budesonide suppository used at this includes 0.5mg budesonides and given for one day
(administration) three times.Alternatively, the one day suppository applied three times containing 500mg 5-aminosalicylic acids.
US 5,449,520 discloses the pharmaceutical composition for rectally, and it is included in Topically active on colon and (risen
Effect) medicament.Rectal foams agent disclosed at this includes mesalazine or budesonide as active constituents of medicine.
WO2015/073846 describes a kind of method for treating ulcerative colitis, wherein using rectal foams agent.The foaming agent
It is the emulsion for including budesonide, propane diols, cetanol, water and suitable additive.
In the utility model DE 297 17 252 of Germany, disclose for treating including for cholestatic liver disease
The medical kit of budesonide and medical comprising urso.One formulation examples be related to comprising cloth how
The suppository of moral, wherein budesonide are suspended in hard fat (tallow).
DE-OS 198 49 737 is disclosed comprising the work being made up of the budesonide and 5-ASA that are suspended in hard fat
Suppository of the property into subassembly.Due to 5-ASA (content) at high proportion, these suppositorys have relatively high weight, therefore also have
Corresponding size.
On the one hand the shortcomings that known drug preparation, is that some patients are not liked using enema or rectal foams agent.It is another
Individual requirement is it is expected following pharmaceutical preparation：It provides active component budesonide in the form of stable storing.
The task of the present invention is to provide the pharmaceutical preparation of the budesonide for rectal administration, its be stable storing and
Pass through the optimised form of active component, denseness (concentration, consistency) and suitably sized and allow painless insertion and appearance
Perhaps targetedly, administration that is local and being confined to rectum.
According to the present invention, the formulation (form of medication) of the suppository by being also referred to as suppository meets these standards.Suppository includes
The active constituents of medicine budesonide of single dose, budesonide can dissolve (pharmaceutical solutions), emulsification (emulsion formulations) and suspend (outstanding
Supernatant liquid preparation) in comprising lipid or water miscible preparation.
Pharmaceutical preparation according to the present invention is height stable storing.The problem of providing suppository (suppository) is, when this
Preparation is in room temperature or slightly elevated temperature (20-30 DEG C) (temperature often occurs during summer or in warmer area)
During lower storage, pharmacological component budesonide is broken down into the relatively low catabolite of abiotic activity or bioactivity.According to
The preparation of the present invention is even also that storage is steady at elevated temperature (20-30 DEG C) within the longer period (12-24 months)
Fixed.It means that after being stored 24 months at 25 DEG C, still at least 90%, preferably at least 95% and preferably at least 97%
The original active component (budesonide) used exists in the form of pharmacological activity.
The present invention relates to the preparation used for rectum, especially suppository, it includes the cloth as therapeutic activity composition
How the salt or derivative and being used for after (insertion) is applied of moral or its pharmaceutically compatible treats the inflammatory disease of rectum (directly
Enteritis).In this case, to selecting suitable base to make high requirement.The base must be chemically stable
With it is inert, and be therefore with active constituents of medicine highly compatible and compatible with mucous membrane, so as to not have during administration
There is mucosal irritation.Further, it must reliably discharge introducing by melting or dissolving at application site after application
Active constituents of medicine.
It is therefore an object of the present invention to the pharmaceutical preparation for rectally of stable storing, the pharmaceutical preparation includes cloth
At least 80 weight % solid fat of the salt or derivative of desonide or its pharmaceutically compatible and the gross weight based on the preparation
The mixture of fat or different hard fats and at least one compatible antioxidant therewith.
In a preferred embodiment of the invention, solid fat of the selection with the small distance between fusing point and freezing point
Fat composition.Fusing point is the temperature of suppository fusing.The fusing point is preferably between about 33.5 DEG C and about 35.5 DEG C, preferably exist
Between 34.0 DEG C and 35.0 DEG C.Freezing point is the temperature that suppository solidifies after the fabrication, i.e., the temperature that suppository solidifies after the fabrication
Degree.According to the present invention, the freezing point is preferably between about 32.5 DEG C and 34.5 DEG C, particularly preferably 33.0 DEG C to 34.0
℃。
In a preferred embodiment, hard fat used according to the invention has high content of triglyceride, and its is excellent
Selection of land is higher than 80 weight %, particularly preferably higher than 90 weight % and is especially preferably higher than 95 weight %.
Parameter as the hard fat, it is known that so-called hydroxyl value.According to the present invention, the hard fat used has low
Hydroxyl value, it is in the range of 1-15, preferably 5-15 and particularly preferably 5-10.
Other properties of preferable hard fat are that the content of unrighted acid is less than 1 weight %, particularly preferably small
In 0.5 weight %.
Designed according to the suppository of the present invention for anum administration.Therefore, form as selection causes them can quilt
Easily apply and be considered by Most patients can be well-accepted because they neither cause in administration pain nor
Cause offending sensation.In a preferred embodiment, suppository has so-called " torpedo shape ".Determined by the gross weight of suppository
The size of fixed suppository is also important.Preferably, weight between 0.8g and 1.2g, particularly preferably 0.95g and 1.05g it
Between.
In a preferred embodiment, according to the present invention suppository with every suppository between 1.8mg and 2.2mg, preferably
Budesonide of the ground per suppository between 1.9mg and 2.1mg and especially preferably often suppository 1.95mg and 2.05mg it
Between budesonide amount include budesonide as active component.
In another preferred embodiment, according to the present invention suppository with every suppository between 3.8mg and 4.2mg,
Budesonide preferably per suppository between 3.9mg and 4.1mg and especially preferably per suppository 3.95mg with
The amount of budesonide between 4.05mg includes budesonide as active component.
In accordance with the present invention, it is preferred that suppository only as pharmacological component and does not include in addition comprising budesonide
Pharmaceutical active ingredient.Especially, 5-ASA (5-aminosalicylic acid) is not included particularly preferably according to the suppository of the present invention.Due to
5-ASA is oxidation-sensitive in itself, thus addition 5-ASA can cause the undesirable brown colouration of suppository.
In a preferred embodiment, ascorbyl palmitate (ascorbyl is included according to the suppository of the present invention
Palmitate) it is used as antioxidant.The concentration of the ascorbyl palmitate is preferably 50ppm-200ppm, particularly preferably
Ground 125-175ppm and especially preferably 150ppm.
It is that budesonide exists with Micronised form in terms of present invention further optimization.Micronised form means activity
The particle size of composition is very small, wherein 100% particle is less than 10 μm/particle (each particle is less than 10 μm).
The importance of the present invention is the storage stability according to the suppository of the present invention.Storage stability can be by manufacturing
Multiple processing steps of period further improve.On the one hand, the manufacture of suppository can be carried out in the case where excluding oxygen.This can lead to
Operate after nitrogen purging during manufacture or under an inert atmosphere to realize.
On the other hand, preferably melt substance is poured into blister foil during suppository is manufactured, and occurred wherein hard
Change.In a preferred embodiment, it is packaged according to the suppository of the present invention in airtight film.
The commonly known base for using comprising lipid or water miscible preparation as suppository.Preferably, using glycerine
Three esters are as lipid.Hard fat is the hemizygous resulting mixture of the monoglyceride of saturated fatty acid, diglyceride and triglycerides.
Since palm-kernel oil and coconut oil, glycerine list is utilized after the saponification of glycerine and suitable saturated fatty acid and resterification
The ratio of ester, diglyceride and triglycerides can obtain the defined solid fat with certain melting property and certain hydroxyl value
Fat.Therefore, by the selection of aliphatic acid and esterification degree, the property of hard fat can be changed and can influence such as fusion range,
Water absorbing capacity and brittle property.Due to the shortage of unrighted acid, hard fat has stability more more preferable than cupu oil
Property, therefore it is intended only as suppository bases thing and plays very little.
The selection of suitable hard fat is for realizing that required storage stability plays an important role.It is therefore preferable that
Ground uses hard fat described herein, wherein crucial aspect is to realize desired storage stability.In order to realize that storage is steady
Qualitative, especially the ratio of budesonide (active component) and hard fat is also important.
Hard fat preferably used according to the invention is to be based on saturation C12-C18The glyceride of aliphatic acid.They mainly by
Triglycerides forms, and has the diglyceride no more than 15% and the monoglyceride no more than 1%.In manufacture according to the present invention's
In hard fat, plant fat resolves into aliphatic acid and glycerine after purification by means of water at high temperature first.By aliphatic acid
Mixture hydrogenation, fractionation and vacuum distillation, to remove short chain fatty acids first.The C that will preferably use12-C18Aliphatic acid is adjusted to
Suitable mixture and with purified glycerine esterification.The reactant mixture is then further purified, especially by washing,
Vacuum drying, the processing for removing dyestuff and steam distillation.It is preferred that the hard wax used includes at least 85%, preferably at least 90%
C12-C18Fatty acid chain.It is also important that the hydroxyl value of hard fat, which is preferably less than about 10,.Hydroxyl value is mainly attributed to glycerine list
Ester (because these two hydroxyls of offer from glycerol residue) and the diglyceride with free hydroxyl group.Hydroxyl value can be by as follows
Measurement：Measure neutralizes the amount of the KOH needed for the acetic acid amount consumed due to acetylation hard fat.That is, hydroxyl value represents
The quantity of free hydroxyl group based on hard fat.Because hard fat used according to the invention is generally during the purifying of glycerine
Release, thus hydroxyl value is the instruction of monoglyceride and/or diglyceride in hard fat mixture be present.If in solid fat
Other additive contributive to free hydroxyl group in fat mixture be present, then they also influence hydroxyl value.
The other key character value (parameter) of hard fat used according to the invention is iodine number.Iodine number represents 100g and consolidated
The grams of the halogen (iodine) of body fat mixture consumption.Consumption for halogen, discuss first be unsaturated compound i.e. not
Saturated fatty acid.Due to very low according to the ratio of the invention, therefore it is less than for kind (qualities) iodine number to be used
3rd, 2 are preferably less than.
The key character value of suppository bases thing also has peroxide number.The value, which is reflected in 1000g suppository bases things, to be present
Active oxygen the peroxide in terms of milliequivalent amount.In suppository bases thing used according to the invention, with meq O/kg
The peroxide number provided is at most 5, preferably no more than 3, particularly preferably at most 1.
In addition to the suppository bases thing comprising lipid, also using the water miscible base being dissolved in present in rectum in liquid
In the material of polyethylene glycol.Preferably, using Macrogol 6000 or HMW and the mixture of low molecule amount.Based on final
Preparation, the content of the additive based on polyethylene glycol between 0 and 20, preferably between 0 and 5, particularly preferably 0.1 to
3 weight %.If component as use, it must be noted that to ensure at most 5meq O/kg low peroxide number.
Budesonide is the glucocorticoid for having high local anti-inflammatory effect.The material in fact may be practically insoluble in water
(0.014mg/ml, Merck index), however, due to its lipophilic property, significant amount be dissolved in organic solvent such as ethanol, methanol and
In chloroform.Depending on the medium used, the material of dissolving is more or less unstable.This unstability in particular budesonide
Oxidative degradation result.Therefore, in the case of no any further step, it is commonly known comprising lipid or
The administration of water miscible base is not a kind of selection for the budesonide suppository for manufacturing stable and compatible, because dissolving
Active constituents of medicine fast degradation in those excipient.
As described in embodiment 1, after being stored 3 months under 25 DEG C/60% relative humidity, different cultivars is consolidated
Body fat simple budesonide suppository (H15,W45) content of display about 10% reduces.By
In being inherently present in the matrix or formation peroxide with trace, the mixture of budesonide and polyethylene glycol is in itself
Incompatible, and due to the suppository after application caused by local mucous membrane stimulate and be used to treat the inflammation of rectum without representing
The alternative solution of property disease.
By contrast, not the shortcomings that prior art not being shown according to the budesonide suppository of the present invention.Here, the present invention is only logical
I.e. at least two, preferably at least three measures being listed below of combination of measure are crossed to realize the target specified (measure
Each individually it is not enough to realize the target specified).
It is therefore an object of the present invention to the budesonide suppository for the stable and compatible that can be obtained by following measure：
(a) budesonide is used as active constituents of medicine using suitable size distribution,
(b) suitable hard fat kind is selected,
(c) ascorbyl palmitate is added by hard fat base as antioxidant using the concentration of optimization,
(d) best ratio of adjustment dissolving and the budesonide being suspended in hard fat base,
(e) using to the application optimal suppository form and size；With
(f) casting film (casting films) of low oxygen permeability is used as packaging.
Preferably, two or more (that is, 3,4,5 or 6) of the measure are combined.
Application according to the present invention is compound and the budesonide suppository of preparation has enough stability, and it allows suppository to exist
Store and apply at least 24 months under the environmental condition of 25 DEG C/60% relative humidity.Meanwhile by present invention ensure that, according to this
The administration of the suppository for treating symptom (indication) of invention can be carried out to without pain due to its size and form, and
And after suppository is inserted, the active constituents of medicine part of suspension is from the base rapid subsidence of melting to impacted membranous part
Position, and the part dissolved is spread out from base.Therefore ensure that the patient compliance (compliance) and work(of budesonide
Both effects are possibly realized within sufficiently long a period of time.
For preparing stable budesonide suppository, the lipophilicity base of hard fat type is particularly suitable to.Tool
There is the hard fat type of high content of triglyceride (at least about 85%) and low hydroxyl value (5-15) therefore to have proved to be special
It is not preferable.Hard fat is substantially made up of the mixture of different monoglycerides, diglyceride and triglycerides.Depend on
The composition of hard fat, thus causes the free OH group of varying number, and it then causes different property.Therefore, solid fat
One characteristic value of fat is hydroxyl value.Above all hydroxyl value<15 hard fat type.Because the quantity of free OH group is few,
For these suppository bases things almost not with hydrolysis sensitive materials or with free acid group material incompatibility.Compare
Under, the usual hard fat with high hydroxyl value does not almost ftracture with good emulsibility during solidification.So
And the trend of after-hardening can be observed, and be possible with the incompatibility of active component.However, have<15 low hydroxyl value
Hard fat there is low emulsibility, be more often intended to ftracture and show low after-hardening trend during solidification.
In accordance with the present invention it is preferred that using the hard fat type contained as far as possible less or without unrighted acid, because
Unsaturated compound is often subjected to oxidation reaction and can degenerated (rancidify).The quantity of unsaturated bond can pass through in lipid
Iodine number determines (Ph.Eur.2.5.4).
Hard fat is made up of the mixture of monoglyceride, diglyceride and triglycerides.By the aliphatic acid of esterification and
Change on composition, the fusing point of hard fat can change.
It is preferred that the commercially available type used isH 15.The particularly preferred kind mainly includes saturated fat
Sour (iodine number≤3), the small distance being characterised by between fusing point (33.5-35.5 DEG C) and freezing point (32.5-34.5 DEG C), and
And only there is the trend of low after-hardening after (cast) is poured out.Ensured using this base, budesonide suppository is in body
Temperature is lower to melt simultaneously discharge active component.
Surprisingly it has been shown that only following combination allows to manufacture the budesonide suppository of stable storing：Molecule point
The scattered active component being dissolved in and be suspended in particularly preferred hard fat kind.This solution and suspension in suppository
The further stabilisation measure of optimum organization permission of liquid formulation must only be limited to the part dissolved of active component.Such as embodiment
Described in 2, budesonide is in particularly preferred hard fat kindSolubility in H 15 is 1.5mg/g.Profit
With the saturated concentration, dosage solubility of the active component in base can be calculated, so as to which targetedly selection stabilizes institute
The amount of the antioxidant needed.
In the case where being respectively 2mg or 4mg budesonide dosage and 1.8g suppository quality, for 2mg form, 100%
Dosage (pure solutions suppositories) in the form of molecule dispersing and dissolving is present, and for 4mg form, dissolving ratio is 67.5% (molten
The combinatory variants of liquid and suspension suppository).
It is therefore preferred that budesonide and the weight ratio of suppository quality (total) are 1-10 to 1000, particularly preferably 1-
5 to 1000.
1g is targetedly reduced to from 1.8g according to currently preferred only suppository quality and causes phase for 2mg-4mg
The dosage range of prestige can realize combination suppository variant.In the case of budesonide 2mg suppositorys, then 75% dosage is to dissolve
Form is present, and 25% dosage exists with suspended form.For budesonide 4mg suppositorys, ratio is 37.5% (dissolving portion
Point) and 62.5% (floating parts).This ensures the antioxidant that can add optium concentration, its only to 37.5% to 75.0% it is molten
The active component part effect of playing stably of solution.The physics and chemistry of the only this preparation found in a manner of surprising are steady
Surely the compound interaction changed just allows budesonide suppository long-time stability at ambient conditions and therefore exempted in ice
Stored in case.
In quality from the case that 1.8g is reduced to about 1g, budesonide suppository obtains particularly preferred for application simultaneously
Size and dimension, sorely inserted without any so as to can ensure that.
According to the suppository of the present invention with about 0.8-1.2g, preferably 0.9-1.1g and particularly preferably 0.95-1.05g
Weight.
As described in example 1 above, active component part of the molecule dispersing and dissolving in hard fat base must pass through
The excipient for adding antioxidation stabilizes.Antioxidant acts as free radical scavenger or serves as itself and can easily aoxidize
And therefore can the not oxidized material of protection activity composition excipient group.
It has now been found that, surprisingly it is being generally used for the antioxidant of non-aqueous (non-aqueous) lipophile system
Such as among ascorbyl palmitate, DL- alpha-tocopherols and butylated hydroxyanisole (BHA), only ascorbyl palmitate is demonstrate,proved
It is bright to be suitable for stabilizing.The result that the display selection of embodiment 3 is attempted.It is surprising that it is turned into actually required antioxygen
With on the contrary, excipient DL- alpha-tocopherols and butylated hydroxyanisole (BHA) even enhance budesonide in hard fat base
Degraded.
Have shown that using the ascorbyl palmitate in 50ppm to 250ppm concentration range be especially suitable
's.Embodiment 4 shows that ascorbyl palmitate stores 24 to budesonide 2mg suppositorys under 25 DEG C/60% relative humidity
The concentration correlation effect of Impurity Distribution (pollution condition) during month.With the not stabilized budesonide suppository phase of embodiment 1
Than only the measure allows to be dissolved in the steady in a long-term of the active component part in hard fat, wherein preferably 100ppm is extremely
200ppm ascorbyl palmitate concentration range is effective.1g and optimization addition are reduced in described suppository quality
In the case of 100ppm ascorbyl palmitate, therefore budesonide suppository can be prepared, it is in 25 DEG C/60% relative humidity
Lower stabilization at least 24 months and it need not be stored in refrigerator.
The composition of the preferred embodiment of budesonide 2mg and 4mg suppository is described in embodiment 5.Here, it will melt
The suppository material of (melting) is poured into the mold of plastics, material then quick solidification wherein.Dosage is each single suppository
Volume.
For receiving the composite membrane of melt preferably by coated with polyvinylidene chloride (40g/m2) and low density polyethylene (LDPE)
Polychloroethylene film (LDPE/PVC/PVdC) composition of 100 μ m-thicks of (40 μm).The mold is the stop work(to oxygen with enhancing
Can packaging material and represent for preparation other protection mechanism.When the mold that aluminium foil is selected for budesonide suppository
When, it still can strengthen stop protection.
In a preferred embodiment, prepared in a nitrogen atmosphere completely according to the suppository of the present invention.It means that
After adding each component of (assembling) final pharmaceutical preparation, air is emptied, then uses nitrogen or inert gas plenum so that
Oxidation reaction does not occur.Then, the suppository material of the thawing of active composition is sent directly into the air-tightness composite membrane of preparation
In (they are hardened wherein).Here, design composite membrane so that they provide final suppository shape, and after filling
It can close so that contact of the oxygen with suppository material can be substantially avoided.
By the measure according to the present invention, the budesonide suppository of stable storing at room temperature can be prepared.The guarantor of embodiment 6
Prove with depositing the result impressive of life test, selected stabilisation measure and the combination of protection mechanism to carry
For stable budesonide suppository.
The particle size of active component budesonide should be as small as possible.Therefore, in suitable grinding machine (such as aeropulverizer)
Budesonide is micronized.According to the present invention, carry out micronizing and cause 100% particle to be less than 10 μm.By the cloth through micronizing
Desonide is mixed in the hard fat melted via the powder supply station of online homogenizer.Here, abrasive grains aggregation and
Realize undissolved part being uniformly distributed in base of active component.The reduction of particle size is also just to prevent from living from beginning
Property composition sedimentation appropriate means.It is also important that particle, which does not lump,.Usual particle is smaller, and the risk of particle agglomeration is bigger,
Since as particle size reduces, the surface area increase and therefore surface energy increase of single particle.By adding a small amount of table
Face activating agent (is typically less than 0.5 weight %, based on the budesonide formulation through micronizing), can prevent the wind of granular grows
Danger.The addition of surfactant can also result in diffusion and wetting of the improved active component in rectum fluid.It is important, however, that
Selection does not cause the surfactant of any undesirable side reaction in the administration of suppository.
For therapeutical uses, active constituents of medicine budesonide is used with 2mg to 4mg dosage.Here, active component with
Micronised form uses, wherein 100% particle is less than 10 μm, at least 95% particle is less than 5 μm, and at least 80% particle is small
In 3 μm.The measure of the particle size distribution of budesonide is carried out by laser diffraction analysis (laser diffractometry).Here, cloth
How moral hygroscopic water is dispersed in water-based (aqueous) medium.After particle is irradiated with one-wavelength laser, diffraction pattern is determined, then can by it
Calculate particle size distribution.The use of micronizing kind prevents the budesonide that suspends during manufacture in the suppository material of thawing
In sedimentation, and therefore allow the uniform active component in the mould poured out and solidified to be distributed.Meanwhile it is micronized and improves
The rate of dissolution of the budesonide of mucous membrane has been settled down to after the insertion and thawing of suppository in rectum fluid.Embodiment 7 shows cloth
The desonide 2mg suppositorys result that release in vitro is tested within the time of 2 hours.Interior during this period, both discharge active component was outstanding
Release is dissolved in the part in hard fat base again for floating part.Therefore, using the preparation according to the present invention, it is ensured that whole cloth
Desonide dosage discharges from preparation and can used on mucous membrane of rectum within the sufficiently long time, therefore has reached treatment effect
Fruit.
It is preferably used for treating the inflammatory disease of rectum according to the suppository of the present invention.These are preferably acute illness herein,
Rapid recovery for its symptom is desirably.
Patient of the treatment with acute (active) proctitis ulcerosa is preferably used for according to the suppository of the present invention.Excellent
In the embodiment of choosing, the suppository with 2mg budesonides or the suppository with 4mg budesonides are once in the morning and once at night administered.
Therefore, according to the budesonide suppository of the present invention particularly suitable for treating acute ulcer rectitis.
(conventional mesalazine bolt is wherein contrasted in the clinical research to the patient with acute ulcer rectitis
Agent, conjoint therapy of the embodiments of the present invention either individually or as the mesalamine suppository with routine is studied), can
Confirm to cause the time until clinical symptom disappearance to substantially reduce using according to the budesonide suppository of the present invention.In clinical research
Middle first day be defined as the terminal with three Consecutive Days that 0 is scored at for hemoproctia and defecation frequency.
Show that alleviation or its symptom are improved under clinical and endoscopy in those of with budesonide suppository in treatment
The ratio of patient is higher.Have≤1 in terms of DAI-UC index (Disease Activity Index-ulcerative colitis) of the patient in change
Value when, realize and alleviate under clinical and endoscopy, wherein the result in hemoproctia and defecation frequency classification is necessary for 0,
And at least 1 point of reduction in subclass " mucous membrane outward appearance " must be realized.The improvement of symptom needs total score at least >=3 point
Reduce.
With preparation as a comparison test mesalamine suppository compared with, have reduced suppository quality according to the present invention
The treatment of budesonide suppository also obtain higher acceptance (degree of recognition) in patients.
In the particular of the present invention, use is according to the present invention during the combination treatment with mesalamine suppository
Budesonide suppository.Such combination treatment is preferably：Budesonide suppository is each administered in the morning and is administered at night
Mesalamine suppository, or mesalamine suppository is administered in the morning and budesonide suppository is administered at night.
In order to evaluate the effect of suppository, using modification such as by Kamm et al. UC-DAI evaluation criterions (2007,
Gastroenterology,132,p.66-75).Explicitly with reference to table disclosed in there 1 and the related definition of parameter.
It is illustrated by the following examples the preferred embodiment of the present invention.
Embodiment 1：Hard fat is in hard fat of the budesonide in the case of not stabilized in different cultivars
The influence of degraded
Table 1
In the case of no any further stabilisation measure, the budesonide 2mg suppositorys of hard fat type are not
Stable, influenceed wherein the property of the hard fat used also has on stability.After the storage time of 3 months,
The content of display 10% or more is reduced under 25 DEG C/60% relative humidity.Here, using hard fat typeW45
Budesonide stability substantially not as using kindH15 situation.Due to monoglyceride and diglyceride
Low content,H15 has low hydroxyl value, andW45 has the monoglyceride and glycerine two of high level
Ester.Therefore, forH15, it is mutual between the free hydroxyl group of hard fat and the functional group of active ingredient molecule
The possibility of effect reduces.
Embodiment 2：Budesonide is in hard fat typeIn saturation solubility
In thawing at 40 DEG CThe dissolubility of budesonide is determined in H15.Here, in hard fat base
The budesonide of suspension incrementss in plinth thing.It is undissolved be partially separated the solidification with suppository mass after, use HPLC/UV
It is following respectively to determine ratio dissolve or undissolved：
Table 2
Therefore, the budesonide determined at 40 DEG C existsSaturated concentration in H15 is about 1.5mg/g.Having
In the 1g suppositorys for having the amount of 2mg budesonide agent, 75% active ingredient molecule dispersing and dissolving is right in hard fat base
In 4mg dosage be 55%.Therefore, it is solution and the mixture of suspension preparation according to the budesonide suppository of the present invention.Only cloth
The dissolving part of desonide must be stabilized by adding antioxidant.
Exist to determine budesonideSaturated concentration in H15, it is standby with different budesonide dosimetric systems
1g suppositorys, and placed 24 hours at 40 DEG C.Then, (10 minutes, with 4000rpm) are centrifuged with settling undissolved cloth
Nai De.Finally, suppository is solidified 2 hours in refrigerator (2-8 DEG C).In order to determine budesonide concentration, suppository is divided into two
Different ratios (bottom and top with suppository tip).Described two parts are individually handled to carry out HPLC containing measurement
It is fixed, then analyze.By the part individually weighed and the content value obtained, calculate budesonide concentration (in terms of mg/g).Cloth
The dissolving part of desonide is evenly distributed in suppository bases thing, and undissolved part is accumulated in suppository tip.Therefore,
The result of budesonide assay in suppository top represents the dissolving part of budesonide.These values are seen in table.
Embodiment 3：It is suitable for stabilizing in hard fat typeThe budesonide dissolved in H15 it is anti-oxidant
The selection of agent
In order to select to test, different antioxidants described in the prior are tested.Here, using has 1.8g mass
Budesonide 2mg suppositorys, it, which is included, is dissolved completely in active component in hard fat base.With the 100ppm's of preparation
Concentration adds antioxidant.Control batch is free of antioxidant.As mold, using by coated with low density polyethylene (LDPE) (LDPE)
Polychloroethylene film (PVC) composition composite membrane, it does not include other polyvinylidene chloride (PVdC) barrier layer.Suppository is existed
Stored 30 days under 30 DEG C/65% relative humidity.After preparation and storage, the impurity point of budesonide suppository is determined with HPLC/UV
Cloth.Following two forms summarize the preparation and result of test.
Table 3
1Size distribution：100%<10 μm, >=95%<5 μm, >=80%<3μm
Table 4
In the case of no addition antioxidant (control batch, batch V1917), under 30 DEG C/65% relative humidity
About 5% Budesonide degradation (see also embodiment 1) can be observed in 30 days.100ppmDL- alpha-tocopherols and butylhydroxy
The addition of methyl phenyl ethers anisole does not cause the stabilisation of suppository (referring to batch V1915 and V1916).It is surprisingly, anti-oxidant at these
The degraded of active component even dramatically increases in the presence of agent.Therefore, DL- alpha-tocopherols and butylated hydroxyanisole (BHA), which do not represent, is used for
Stabilize the selection of budesonide suppository.On the contrary, ascorbyl palmitate shows significant antioxidation.In storage time
Period, not it is observed that the degraded of budesonide.Experiment is to the unfavorable condition of budesonide stability (such as active component
Being completely dissolved property in hard fat and without any further oxygen barriers casting film use) under carry out,
So that the antioxidation of ascorbyl palmitate can be shown.
Embodiment 4：As for stabilizing in hard fat typeThe antioxygen of the budesonide dissolved in H15
The optium concentration of the ascorbyl palmitate of agent
Using following budesonide 2mg suppositorys prescription test as the anti-of the antioxidant for stabilizing budesonide
The effect of bad hematic acid palmitate：
Table 5
1Size distribution：100%<10 μm, >=95%<5 μm, >=80%<3μm
Therefore, for all suppository, it is dissolved in hard fat base and the ratio of budesonide to be stabilized
Example is 75%.As mold, LDPE/PVC/PVdC composite membrane is used.24 are manufactured and stored under 25 DEG C/60% relative humidity
After individual month, the Impurity Distribution of budesonide suppository is determined using HPLC/UV.The result of acquisition is as follows：
Table 6
Depending on concentration, cloth of the stable chemoattractant molecule dispersing and dissolving of ascorbyl palmitate in hard fat base
Nai De.The preferred embodiment of budesonide 2mg and 4mg suppository is anti-bad in 100ppm-150ppm concentration range
Hematic acid palmitate.
Embodiment 5：The qualitative and quantitative composition of the preferred embodiment of budesonide 2mg and 4mg suppository
Table 7
1Size distribution：100%<10 μm, >=95%<5 μm, >=80%<3μm
Embodiment 6：The preservation life test of the preferred embodiment of budesonide 2mg and 4mg suppository
Budesonide 2mg and 4mg suppository is prepared using 100ppm ascorbyl palmitates in a preferred embodiment
And stored under 25 DEG C/60% relative humidity to carry out preservation life test.With rule after the fabrication and during storage
The interval of rule determines the content and purity of suppository using HPLC/UV.Following two forms summarize budesonide 2mg suppositorys and cloth
The result of desonide 4mg suppositorys.
Table 8
Table 9
Budesonide content and catabolite sum only slightly change during storage.Due to being sent out in a manner of surprising
The combination of existing physics and chemical stabilization, the shelf-life (preserving the life-span) of budesonide 2mg and 4mg suppository is 25 DEG C/60%
At least time of 24 months is ensured under relative humidity.
Embodiment 7：The release in vitro test of budesonide 2mg suppositorys
According to budesonide suppository discharge active component within the time of 2 hours that is of the invention compound and preparing.At this moment
In, suspend and with active component part existing for Micronised form and molecule dispersing and dissolving in hard fat base
Active component is released both part.This ensures that active component can be used and can on mucous membrane of rectum within the sufficiently long time
Play its therapeutic effect.Fig. 1 be shown in after manufacture (T0) and stored under 25 DEG C/60% relative humidity 24 months (T24) it
Afterwards, the release profiles of batch V2042 budesonide 2mg suppositorys.Measure is in 37 DEG C of progress, preferably by being retouched in European Pharmacopoeia
The flow cell (equipment 4) stated, it is operated using the flow velocity of 16ml/ minutes as closed system.Using added with 0.5% 12
The citrate phosphate buffer pH 6.8 of sodium alkyl sulfate is used as culture medium.In order to describe release dynamics, 15,
30th, sampled after 45,60,90 and 120 minutes.The budesonide being dissolved in release culture medium is determined with HPLC/UV.
Embodiment 8：The Receptive inspection of clinical efficacy and patient to suppository
In double-blind study, budesonide suppository is tested to the patient for suffering from rectitis.79 patients have been treated altogether, its
In test the different suppositorys with different activities composition, and patient not exactly knows which kind of suppository they receive.
During these tests, it is determined that find that clinical remission (is defined as " first day ", had after which period
≤ 3 defecation/days, wherein all must be in excrement without blood).Using the suppository according to the present invention, the period is in intermediate value
For 8 days.
As other parameter, measure shows the percentage of the patient of mucous membrane rehabilitation, and wherein this is by shadow via enteron aisle
Ring the endoscopy determination of part and (the UC-DAI/ ulcerative colitis-diseases of amendment are lived as Disease Activity Index
Sex index) appropriate section measurement.The value is 81%.With the budesonide suppository with 4mg active components according to the present invention
The result that (1g gross weights) obtains is summarized in table 10 below.
Table 10
As another importance to be played a significant role using only suppository, the suppository according to the present invention is checked in patient
In acceptance.Here, data are collected via corresponding questionnaire, wherein the administration in the morning of inquiry suppository and influence (damage
Evil).For first problem, " how you, which evaluate, uses suppository morning", patient's available " easily/less difficult/difficulty " is back and forth
Answer.For Second Problem, " your daily life is influenceed in much degree using suppository in the morning", patient is available " quite
Greatly/less big/does not almost have " answer.
The result of survey of patients is summarized in table 11 below.
Table 11
In a word, it could be assumed that, administration in the morning is judged as simply and readily by Most patients (78.5%).This
Outside, Most patients (58.2%) find in the morning to have little to no effect daily life using suppository.
These data are shown, are not only stable storing according to the suppository of the present invention, but also have extraordinary clinic
Effect, while highly received by patient.
Claims (16)
1. for the pharmaceutical preparation of rectally, the pharmaceutical preparation includes budesonide or the salt or derivative of its pharmaceutically compatible
At least 80 weight % hard fat or the mixture of different hard fats of thing and gross weight based on the preparation and
At least one compatible antioxidant therewith.
2. preparation according to claim 1, it is characterised in that it has the small distance between fusing point and freezing point, wherein institute
Fusing point is stated between 33.5 DEG C and 35.5 DEG C, and the freezing point is between 32.5 DEG C and 34.5 DEG C.
3. according to the preparation of one of claim 1 or 2, it is characterised in that the hard fat has high content of triglyceride i.e.
The hydroxyl value of >=80 weight %, 1-15 and the unrighted acid comprising less than 1 weight %.
4. according to one of claim 1-3 preparation, it is characterised in that it is the suppository for anum administration.
5. preparation according to claim 4, it is characterised in that it includes the budesonide per suppository 1.8-4.2mg.
6. preparation according to claim 5, it is characterised in that it includes the budesonide per suppository 1.8-2.2mg.
7. preparation according to claim 5, it is characterised in that the weight per suppository is between 3.8 and 4.2mg budesonides.
8. according to the preparation of one of preceding claims, it is characterised in that the weight per suppository is between 0.8 and 1.2g.
9. according to one of claim 1-8 preparation, it is characterised in that the antioxidant is ascorbyl palmitate.
10. preparation according to claim 8, it is characterised in that ascorbyl palmitate is deposited with 50ppm-200ppm concentration
.
11. according to one of claim 1-10 preparation, it is characterised in that budesonide exists with Micronised form, wherein
100% particle is less than 10 μm/particle.
12. according to one of claim 1-11 preparation, it is characterised in that the pharmaceutical preparation of stable storing is to exclude the feelings of oxygen
Prepared under condition.
13. according to one of claim 1-12 preparation, it is characterised in that the pharmaceutical preparation is with the bolt in air-tightness casting film
The form packaging of agent.
14. it is used for the purposes of inflammatory disease for treating rectum according to one of claim 1-13 pharmaceutical preparation.
15. it is used for the purposes for treating acute ulcer rectitis according to one of claim 1-13 pharmaceutical preparation.
16. according to the purposes of one of claims 14 or 15, the pharmaceutical preparation is combined with mesalamine suppository.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP15175806.7A EP3115037B1 (en) | 2015-07-08 | 2015-07-08 | Pharmaceutical preparations for the treatment of inflammatory conditions of the rectum |
| EP15175806.7 | 2015-07-08 | ||
| PCT/EP2016/064907 WO2017005524A1 (en) | 2015-07-08 | 2016-06-28 | Pharmaceutical formulation for the treatment of inflammatory changes to the rectum |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107847435A true CN107847435A (en) | 2018-03-27 |
| CN107847435B CN107847435B (en) | 2021-07-27 |
Family
ID=53540667
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201680039904.2A Active CN107847435B (en) | 2015-07-08 | 2016-06-28 | Pharmaceutical formulation for treating inflammatory changes of the rectum |
Country Status (23)
| Country | Link |
|---|---|
| US (3) | US10905699B2 (en) |
| EP (2) | EP3115037B1 (en) |
| JP (1) | JP6857644B2 (en) |
| CN (1) | CN107847435B (en) |
| AU (1) | AU2016290343B2 (en) |
| CA (1) | CA2986081C (en) |
| DK (1) | DK3319586T3 (en) |
| EA (1) | EA033153B1 (en) |
| ES (2) | ES2688119T3 (en) |
| FI (1) | FI3319586T3 (en) |
| HR (1) | HRP20230174T1 (en) |
| HU (1) | HUE061585T2 (en) |
| IL (1) | IL255247B (en) |
| LT (1) | LT3319586T (en) |
| MA (1) | MA42367B1 (en) |
| MD (1) | MD3319586T2 (en) |
| PL (1) | PL3319586T3 (en) |
| PT (2) | PT3115037T (en) |
| RS (1) | RS64020B1 (en) |
| SI (1) | SI3319586T1 (en) |
| UA (1) | UA120075C2 (en) |
| WO (1) | WO2017005524A1 (en) |
| ZA (1) | ZA201707777B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022226778A1 (en) * | 2021-04-27 | 2022-11-03 | 广州共禾医药科技有限公司 | Rectally administered pharmaceutical composition containing oseltamivir or pharmaceutically acceptable salt thereof, and preparation method therefor and use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE29717252U1 (en) * | 1997-09-26 | 1998-02-19 | Dr. Falk Pharma GmbH, 79108 Freiburg | Drug kit consisting of a budesonide-containing and an ursodeoxycholic acid-containing drug for the treatment of cholestatic liver diseases |
| WO2000024388A2 (en) * | 1998-10-28 | 2000-05-04 | Dr. Falk Pharma Gmbh | Combination of 5-aminosalicylic acid and a budesonide, 6-methyl prednisolone or prednisolone for treating inflammatory disorders of the intestinal tract |
| CN1738602A (en) * | 2002-12-27 | 2006-02-22 | 遗传工程与生物技术中心 | Formulations for the rectal administration of thrombolytically-active agents |
| CN102525883A (en) * | 2010-12-09 | 2012-07-04 | 丽珠集团丽珠制药厂 | Voriconazole suppository and preparation method and application thereof |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB701831A (en) * | 1950-10-19 | 1954-01-06 | Rudolf Von Wuelfing | Process for the production of suppositories containing medicaments |
| US3208907A (en) * | 1961-11-13 | 1965-09-28 | Lab Toraude | Stabilized salicylate compositions |
| DE3709861A1 (en) * | 1987-03-25 | 1988-10-06 | Henkel Kgaa | EMULSIFYING SUPPOSITORIES AND MEASURES PRODUCED FROM THEM |
| JP2927830B2 (en) * | 1989-09-01 | 1999-07-28 | 東京田辺製薬株式会社 | Danazol suppository |
| IT1243379B (en) | 1990-07-27 | 1994-06-10 | Giuliani Spa | PHARMACEUTICAL COMPOSITION SUITABLE FOR RECTAL ADMINISTRATION OF ACTIVE PRINCIPLES WHICH EXPLICATE A MEDICATION ACTION AT THE LEVEL OF THE COLON, PREVALENTLY TOPICAL |
| US20020085978A1 (en) * | 2000-11-10 | 2002-07-04 | Mina Buenafe | Degradation-resistant glucocorticosteroid formulations |
| JP5223307B2 (en) * | 2006-11-17 | 2013-06-26 | 大正製薬株式会社 | Suppository |
| EP2392321A1 (en) * | 2007-06-13 | 2011-12-07 | Jay Pravda | Combined composition for rectal administration for the treatment of inflammatory bowel disease |
| CN102316889B (en) * | 2008-11-26 | 2014-11-26 | 萨蒂奥根制药公司 | Compositions containing satiogens and methods of use |
| WO2012022796A2 (en) * | 2010-08-20 | 2012-02-23 | Boehringer Ingelheim International Gmbh | Novel combinations |
| WO2015073846A1 (en) | 2013-11-15 | 2015-05-21 | Salix Pharmaceuticals, Inc. | Method of treating ulcerative colitis |
-
2015
- 2015-07-08 ES ES15175806.7T patent/ES2688119T3/en active Active
- 2015-07-08 EP EP15175806.7A patent/EP3115037B1/en active Active
- 2015-07-08 PT PT15175806T patent/PT3115037T/en unknown
-
2016
- 2016-06-28 CN CN201680039904.2A patent/CN107847435B/en active Active
- 2016-06-28 RS RS20230170A patent/RS64020B1/en unknown
- 2016-06-28 HR HRP20230174TT patent/HRP20230174T1/en unknown
- 2016-06-28 US US15/742,710 patent/US10905699B2/en active Active
- 2016-06-28 LT LTEPPCT/EP2016/064907T patent/LT3319586T/en unknown
- 2016-06-28 PL PL16732617.2T patent/PL3319586T3/en unknown
- 2016-06-28 CA CA2986081A patent/CA2986081C/en active Active
- 2016-06-28 PT PT167326172T patent/PT3319586T/en unknown
- 2016-06-28 HU HUE16732617A patent/HUE061585T2/en unknown
- 2016-06-28 EA EA201792685A patent/EA033153B1/en unknown
- 2016-06-28 FI FIEP16732617.2T patent/FI3319586T3/en active
- 2016-06-28 MA MA42367A patent/MA42367B1/en unknown
- 2016-06-28 SI SI201631664T patent/SI3319586T1/en unknown
- 2016-06-28 DK DK16732617.2T patent/DK3319586T3/en active
- 2016-06-28 EP EP16732617.2A patent/EP3319586B1/en active Active
- 2016-06-28 AU AU2016290343A patent/AU2016290343B2/en active Active
- 2016-06-28 UA UAA201800685A patent/UA120075C2/en unknown
- 2016-06-28 JP JP2018500330A patent/JP6857644B2/en active Active
- 2016-06-28 MD MDE20180489T patent/MD3319586T2/en unknown
- 2016-06-28 WO PCT/EP2016/064907 patent/WO2017005524A1/en active Application Filing
- 2016-06-28 ES ES16732617T patent/ES2938358T3/en active Active
-
2017
- 2017-10-24 IL IL255247A patent/IL255247B/en active IP Right Grant
- 2017-11-16 ZA ZA2017/07777A patent/ZA201707777B/en unknown
-
2020
- 2020-11-10 US US17/094,233 patent/US11738032B2/en active Active
-
2023
- 2023-07-12 US US18/221,164 patent/US20230364113A1/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE29717252U1 (en) * | 1997-09-26 | 1998-02-19 | Dr. Falk Pharma GmbH, 79108 Freiburg | Drug kit consisting of a budesonide-containing and an ursodeoxycholic acid-containing drug for the treatment of cholestatic liver diseases |
| WO2000024388A2 (en) * | 1998-10-28 | 2000-05-04 | Dr. Falk Pharma Gmbh | Combination of 5-aminosalicylic acid and a budesonide, 6-methyl prednisolone or prednisolone for treating inflammatory disorders of the intestinal tract |
| CN1738602A (en) * | 2002-12-27 | 2006-02-22 | 遗传工程与生物技术中心 | Formulations for the rectal administration of thrombolytically-active agents |
| CN102525883A (en) * | 2010-12-09 | 2012-07-04 | 丽珠集团丽珠制药厂 | Voriconazole suppository and preparation method and application thereof |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0977562B1 (en) | Methods and compositions for delivery of taxanes | |
| EP0957931B1 (en) | Solid pharmaceutical compositions comprising a cyclosporin and an anionic surfactant | |
| CN105246464A (en) | Stabilized modified release vitamin d formulation and method of administring same | |
| US4786495A (en) | Therapeutic agents | |
| BRPI0515070B1 (en) | SYSTEM OF DELIVERY OF SELF-EMULSIFYING BUTILFTALIDE DRUGS AND PROCESS FOR THE PREPARATION OF THE SYSTEM OF DELIVERY OF SELF-EMULSIFYING BUTILFTALIDE DRUGS | |
| BRPI0609497A2 (en) | improved fenofibrate formulations | |
| JP2008534584A (en) | Improved formulation of fenofibrate-containing menthol or PEG / poloxamer mixture | |
| CN102302447B (en) | Novel taxol lipid microsphere injection and preparation method thereof | |
| Awad et al. | 3D printed multi-drug-loaded suppositories for acute severe ulcerative colitis | |
| US20230364113A1 (en) | Pharmaceutical formulation for the treatment of inflammatory changes to the rectum | |
| CN101375834B (en) | Solid dispersion of Ailamode and preparation method thereof and medicament application | |
| KR101679380B1 (en) | Pharmaceutical composition including dutasteride and capsule formulation comprising the same | |
| US7351431B2 (en) | Freeze-dried pharmaceutical preparation | |
| FR2548539A1 (en) | PHARMACEUTICAL COMPOSITION CONTAINING A LIQUID LUBRICANT AND METHOD FOR IMPROVING THE DISSOLUTION OF HARD GELATINE CAPSULES OR TABLETS CONTAINING THERAPEUTIC FORMULAS AND A LUBRICANT | |
| JP2002511101A (en) | Pharmaceutical composition | |
| CN102048711B (en) | Granisetron membrane preparation and preparation method | |
| CN115120611A (en) | NO donor micelle composition and preparation method and application thereof | |
| BR112015018144B1 (en) | stable pharmaceutical water / oil emulsion composition with manometric oil droplets, method for making the same and single high dose of clopidogrel used to treat a patient | |
| ES2733113T3 (en) | Stable pharmaceutical composition of a water soluble vinorelbine salt | |
| US11690835B2 (en) | Formulation | |
| Elbakry et al. | Spray congealing for enhancement the solubility and pharmacological activity of methylprednisolone | |
| EP1486209A2 (en) | Pharmaceutical formulations for the treatment of inflammatory bowel disease | |
| CN101115487A (en) | Prevention of thrombotic disorders with active vitamin d compounds or mimics thereof | |
| WO2005032516A1 (en) | Formulation and manufacturing process of self-microemulsified aceclofenac soft capsules | |
| JP2003501447A (en) | Transdermal induction of aspirin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1248109 Country of ref document: HK |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |